Certain Vitamin D compounds have been demonstrated to have unique biological activity for treatment of cancers, psoriasis and osteoporosis.
The natural hormone, 1.alpha.,25-dihydroxyvitamin D.sub.3, and many of the 1.alpha.-hydroxyvitamin D analogs possess a high degree of biological activity in animals and humans. As such, many vitamin D compounds are now being used or developed as pharmaceutical products to treat specific diseases such as osteoporosis, cancer, psoriasis, renal osteodystrophy, etc.
The standardized numbering system for the natural hormone, 1.alpha.,25-dihydroxyvitamin D.sub.3, and 19-nor-1,25-dihydroxyvitamin D.sub.3 where the 19-methylene group has been replaced with two hydrogens, is shown below in Formula (1) and Formula (2) which are as follows: ##STR1##
Crystallization of an organic compound (or solute) requires that a solvent be chosen from which a supersaturated solution of the solute can be obtained. This ideal crystallization solvent should possess high solvent power for the substance to be crystallized at elevated temperatures and a comparatively low solvent power at room temperature or below. Heating a suspension of the organic solute in a solvent until a homogeneous solution is obtained and subsequent cooling creates a supersaturated solution from which crystallization occurs. The group of pharmaceutically useful 1.alpha.-hydroxylated vitamin D analogs possess very similar physical-chemical properties and, therefore, are normally crystallized from a very limited number of solvents, most commonly, methyl formate.
A unique group of pharmaceutically useful vitamin D analogs have fluorine atoms substituted for hydrogen atoms on a vitamin D nucleus. These fluorinated vitamin D analogs have been shown to be resistant to metabolic breakdown and possess longer therapeutic lifetimes in the body. A group of hexafluoro-1.alpha.,25-dihydroxylated vitamin D analogs are presently being developed for the treatment of breast cancer, osteoporosis and psoriasis, and a need exists for an effective synthetic method to produce hexa-fluorovitamin compounds of the general formula: ##STR2## Wherein the R group in the above structure represents side chains shown below where: ##STR3## R.sub.1 represents a hydrogen atom, alkyl group, hydroxy group, protected hydroxy group or alkoxy group and X represents straight, branched or cyclic hydrocarbon group, saturated or unsaturated, having 1-12 carbon atoms which may carry one or more substituents selected from, halogen, hydroxy, protected hydroxy, alkoxy or oxo groups. Y.sub.1 and Y.sub.2 represent hydrogen atoms or taken together represent an exocyclic methylene group .dbd.CH.sub.2 and Z.sub.1 and Z.sub.2 which may be the same or different represent a hydrogen, alkyl, hydroxyl, protected hydroxyl or alkoxy group and taken together may represent an oxo group or .dbd.CR.sub.2 R.sub.3 where R.sub.2 and R.sub.3 together or individually represent a hydrogen atom, alkyl group protected hydroxy group or alkoxy group.
The substitution of a fluorine atom for a hydrogen atom also greatly alters the physical-chemical properties of the molecule. In particular, the solubility of fluorinated vitamin D analogs in common organic solvents is greatly enhanced. Therefore, fluorinated vitamin D analogs are resistant to crystallization because supersaturated solutions are difficult to achieve in commonly used crystallization solvents used for vitamin D. This is especially true for the group of hexafluoro-1.alpha., 25-dihydroxylated vitamin D analogs, depicted in the above formula, which can not be crystallized from solvents normally used in the vitamin D field. As potential pharmaceutical ingredients, it would be beneficial to be able to obtain hexafluorovitamin D compounds in crystalline form and to efficiently produce such materials in crystalline form on a commercial scale.
Generally, the crystalline form of chemical compounds are highly desirable for pharmaceutical use. Some of the advantages of active pharmaceutical compounds in crystalline form (as opposed to amorphous liquid or oil form) are that the crystalline form is generally more stable, resistant to oxidative degradation, exhibit improved handleability and, perhaps most importantly, provide a high confidence level of possessing a defined purity and potency. For example, amorphous and other noncrystalline forms of synthesized compounds can include solvents, precursors or other impurities. However, the crystalline form of such compounds inherently have a high level of purity. Consequently, it would be beneficial to be able to obtain hexafluoro-vitamin D compounds in crystalline form.
A need exists for hexafluorovitamin D analogs in crystalline form suitable for pharmacological use. A need also exists for an effective synthesis method to produce hexafluorovitamin D compounds and for a solvent to permit crystallization of such compounds.